Melanin is the natural pigment synthesized in highly specialized cells, melanocytes, present in the skin. The primary biological function of the pigment is to protect the skin tissues against (photo)oxidative damage by scavenging free radicals and reactive oxygen species. Melanin is also present in high quantities in melanoma, a form of pigmented skin tumor, which is highly resistant to chemo- and radiotherapy. The main objective of this research project was to investigate the reaction of DOPA-melanin (DM), a synthetic analog of the natural eumelanin skin pigment, with NO2- radicals. NO2- along with other reactive nitrogen species (RNS) is known to be involved in the antitumor action of macrophages and neutrophils. The radicals were produced by enzymatic oxidation of NO2- using lactoperoxidase (LP)/H2O2 system. The interaction of DM with NO2- was measured by monitoring changes in the melanin natural EPR signal. We found that the exposure of DM to NO2- produces new radicals in the pigment as evidenced by an increased intensity (up to 10-fold) of its EPR signal. The content of the radicals in DM was dependent on [NaNO2],[LP], and [H2O2], reaching a clearly developed maximum at specific nitrite and LP concentrations. The existence of this maximum implies that NO2- both generates and destroys the melanin semiquinone radicals. This study provides the first compelling evidence for the scavenging of NO2- radicals by melanin. The process is very efficient and suggests that melanin pigments may be involved in intracellular management of certain RNS, such as NO2- radicals. Biological consequences of the scavenging of NO2- by melanin have to be investigated. In future studies we intend to investigate the interaction of melanin with other reactive nitrogen species, and the role of RNS in melanin biosynthesis.